The proposed research represents a testing of the following hypothesis regarding the origin of genetic muscular dystrophies: We believe that dystrophies observed in laboratory animals, as well as certain forms of human dystrophy, are the result of a systemic membrane anomaly which leads to increased permeability to potassium ion. Muscle dysfunction is, then, the result of defective excitation-coupling owing to excessively free potassium movement across regions of the excitable membrane. We shall examine a number of membrane systems in diseased animals with regard to surface ultrastructure (by scanning electron microscopy) and to ion permeability (using specific ion electrodes) in order to see if the disease isreally systemic. We shall investigate energy-coupling in mitochondria from several tissues of affected animals since a potassium leak should lead to profound alterations in ATP synthesis, ion transport, and other energy- linked functions. We shall study potassium-induced excitation in diseased muscle as a possible model for the defect in excitation-coupling. We shall carry out a detailed survey of membrane composition by means of thin-layer and gas chromatography in order to learn what changes underlie the alteration of permeability already observed. Finally, we shall endeavor to find a means of decreasing potassium flux on an organism wide basis in order to see if aspects of the pathology might be reversible. In this last connection, a number of cations have been shown to inhibit potassium transport and we intend to investigate them.